Copper in PET studies

Copper

Copper ion is the catalytic cofactor of many enzymes, and an important structural component for some proteins. Although copper is essential metal, it can also be toxic, and therefore the amount of copper in body is kept under tight control by the liver. Excess copper is removed via hepatobiliary route (Chakravarty et al., 2016). Urinary excretion of intravenously administered Cu2+ is negligible (Avila-Rodriguez et al., 2017). In plasma, Cu2+ is bound to ceruloplasmin and transcuprein; cell surface enzymes reduce Cu2+ to Cu+ for transportation into the cell by copper transporter 1 (CTR1, SLC31A1). Inside the cell, Cu+ ions are tightly bound by copper chaperones, because free copper ions would react with wide variety of protein side chains and copper is a potent inhibitor of many enzymes (Kaplan and Maryon, 2016). Intracellular chaperones transport Cu+ ions further to the target enzymes, including cytosolic SOD1, mitochondrial cytochrome oxidase, and ATP7A/B at the trans-Golgi network (Chakravarty et al., 2016). Trans-Golgi membranes contain Cu-pumps which collect recycled and excess copper in the Golgi, and insert Cu+ into copper-dependent enzymes in the secretory pathway, or traffic excess copper in vesicles to the plasma membrane. Copper works also as cofactor for dopamine β-hydroxylase and peptidylglycine αamidating mono-oxygenase, in neurotransmitter and neuropeptide biosynthesis (Kaplan and Maryon, 2016). Cu-dependent lysyl oxidase is essential in cross-linking collagen in extracellular matrix.

In addition to CTR1, some other transporters may participate in copper transport, such as the divalent metal ion transporter DMT1 (which mainly transports Mn2+ and Zn2+), anion exchanger AE1, and anion transporters in acidic environment (Kaplan and Maryon, 2016). CTR2 is assumed to work as intracellular copper transporter. Efflux of copper is facilitated by ATP7A and ATP7B.

64Cu

64Cu has a half-life of 12.7 h, which is suitable for chelation labelling large-molecule imaging agents that have relatively slow pharmacokinetics (Wadas et al., 2007). It decays by three routes, 45% via electron capture, 37.1% via β- decay, and 18% via β+ decay. 64Cu could also be used in targeted radionuclide therapy.

Most widely used 64Cu-labeled PET radioligand is the hypoxia marker [64Cu]ATSM (Holland et al., 2009). In hypoxic cells Cu2+ is reduced to Cu+, which changes its coordination properties, and causes the dissociation of 64Cu+ from the ATSM; 64Cu+ is then trapped inside hypoxic cells.

A Cu2+ complex Cu-GTSM has been shown to deliver copper across the blood-brain barrier (BBB), releasing it to the cells; that triggered neuroprotective mechanisms in Alzheimer’s disease (AD) mouse model. [64Cu]GTSM uptake was also increased in the AD mice (Torres et al., 2016). In brain studies it should be considered that if [64Cu]Cu2+ is dissociated from the radioligand, amyloid-β peptides bind Cu2+ with high affinity (Atwood et al., 2000), which may hamper the interpretation of the brain uptake.

[64Cu]histidine can be used to measure biliary excretion of copper (Bahde et al., 2012), which is impaired in Wilson’s disease.

64Cu2+

In its ionic form 64Cu2+, usually as chloride ([64Cu]CuCl2), can be used for PET imaging of several types of cancer, because CTR1 is overexpressed in many cancer cell types (Chakravarty et al., 2016). Since 64Cu2+ is not excreted to urine, it may be particularly suitable for detecting tumours in pelvic area, for example prostate cancer (Capasso et al., 2015; Piccardo et al., 2018). Increased uptake in tumours is most likely due to the increased transport, not by vascular leakage, because 64Cu uptake was reduced in CTR1 knockdown tumour mice (Cai et al., 2014). Increased uptake has also been observed in traumatic brain injury (TBI) model (Peng et al., 2015), and in healthy ageing in mice (Peng et al., 2018). The authors claim that 64Cu2+ uptake is not caused by simple leakage due to BBB disruption, but because of activated microglial cells and/or copper/zinc SOD or other copper transporters and chaperones. Muscular inflammation did not lead to increased 64Cu uptake in a mouse model, but muscle injury caused high 64Cu uptake (Xie et al., 2017a).

In mice, 64Cu2+ uptake is very high in the liver, and relatively high also in the heart, kidneys, and liver (Peng et al., 2015; Peng et al., 2018). In humans, 64Cu2+ is also concentrated in the liver, and additionally in bowels, pancreas, and kidneys (Avila-Rodriguez et al., 2017).

Wilson’s disease (WD) is characterized by copper overload which causes liver dysfunction, kidney failure, and neurological problems. WD is caused by an autosomal recessive mutation in ATP7B gene, leading to defective sequestering of copper by ceruloplasmin and impaired excretion into bile (Bartnicka & Blower, 2018). In a mice model of WD, [64Cu]CuCl2 bile excretion was reduced and liver uptake increased after intravenous or oral administration (Peng, 2014). In the same mice model, brain 64Cu uptake was very low but increased by age (Xie et al., 2017b). Copper flux differs by age also in the brain of normal mouse, and age-related changes differ from changes in glucose metabolism (Peng et al., 2018).

62Cu

Half-life of 62Cu is only 9.7 min, and therefore its usage is less limited.


See also:



References:

Avila-Rodriguez MA, Rios C, Carrasco-Hernandez J, Manrique-Arias JC, Martinez-Hernandez R, García-Pérez FO, Jalilian AR, Martinez-Rodriguez E, Romero-Piña ME, Diaz-Ruiz A. Biodistribution and radiation dosimetry of [64Cu]copper dichloride: first-in-human study in healthy volunteers. EJNMMI Res. 2017; 7(1):98. doi: 10.1186/s13550-017-0346-4.

Bartnicka JJ, Blower PJ. Insight into trace metal metabolism in health and disease from PET: “PET Metallomics”. J Nucl Med. 2018; 59: 1355-1359. doi: 10.2967/jnumed.118.212803.

Bulcke F, Dringen R, Scheiber IF. Neurotoxicity of copper. In: Aschner M and Costa LG (eds.): Neurotoxicity of Metals, Springer, 2017, doi: 10.1007/978-3-319-60189-2_16.

Chakravarty R, Chakraborty S, Dash A. 64Cu2+ ions as PET probe: an emerging paradigm in molecular imaging of cancer. Mol Pharmaceutics 2016; 13: 3601-3612. doi: 10.1021/acs.molpharmaceut.6b00582.

Conti M, Eriksson L. Physics of pure and non-pure positron emitters for PET: a review and a discussion. EJNMMI Phys. 2016; 3(1): 8. doi: 10.1186/s40658-016-0144-5.

Elomaa VV, Jurttila J, Rajander J, Solin O. Automation of 64Cu production at Turku PET Centre. Appl Radiat Isot. 2014; 89: 74-78. doi: 10.1016/j.apradiso.2014.02.010.

Gutfilen B, Souza SA, Valentini G. Copper-64: a real theranostic agent. Drug Des Devel Ther. 2018; 12: 3235-3245. doi: 10.2147/DDDT.S170879.

Holland JP, Ferdani R, Anderson CJ, Lewis JS. Copper-64 radiopharmaceuticals for oncologic imaging. PET Clin. 2009; 4: 49-67. doi: 10.1016/j.cpet.2009.04.013.

Hueting R. Radiocopper for the imaging of copper metabolism. J Labelled Comp Radiopharm. 2014; 57(4): 231-238. doi: 10.1002/jlcr.3155.

Jødal L, Le Loirec C, Champion C. Positron range in PET imaging: non-conventional isotopes. Phys Med Biol. 2014; 59(23): 7419-7434.

Kaplan JH, Maryon EB. How mammalian cells acquire copper: an essential but potentially toxic metal. Biophysical J. 2016; 110: 7-13. doi: 10.1016/j.bpj.2015.11.025.

Peng F. Positron emission tomography for measurement of copper fluxes in live organisms. Ann N Y Acad Sci. 2014; 1314: 24-31. doi: 10.1111/nyas.12383.

Peng F, Muzik O, Gatson J, Kernie SG, Diaz-Arrastia R. Assessment of traumatic brain injury by increased 64Cu uptake on 64CuCl2 PET/CT. J Nucl Med. 2015; 56: 1252-1257. doi: 10.2967/jnumed.115.154575.

Shokeen M, Anderson CJ. Molecular imaging of cancer with copper-64 radiopharmaceuticals and positron emission tomography (PET). Acc Chem Res. 2009; 42(7): 832-841.

Smith SV. Molecular imaging with copper-64. J Inorg Biochem. 2004; 98(11): 1874-1901. doi: 10.1016/j.jinorgbio.2004.06.009.

Torres JB, Andreozzi EM, Dunn JT, Sidduque M, Szanda I, Howlett DR, Sunassee K, Blower PJ. PET imaging of copper trafficking in a mouse model of Alzheimer disease. J Nucl Med. 2016; 57: 109-114. doi: 10.2967/jnumed.115.162370.

Wadas TJ, Wong EH, Weisman GR, Anderson CJ. Copper chelation chemistry and its role in copper radiopharmaceuticals. Curr Pharm Des. 2007; 13(1): 3-16.



Tags: ,


Created at: 2017-09-18
Updated at: 2018-10-31
Written by: Vesa Oikonen